Current approaches for treating pain and/or inflammation involve systemic delivery of therapeutic agents. Anti-inflammatory agents target tumor necrosis factor alpha (TNF-α) which appears early in the inflammatory cascade following infection or injury. It is produced by monocytes, macrophages, and T lymphocytes. TNF-α exerts its primary effects on monocytes, synovial macrophages, fibroblasts, chondrocytes, and endothelial cells, and stimulates proinflammatory cytokine and chemokine synthesis. It activates granulocytes, and increases MHC Class II expression. It promotes secretion of matrix metalloproteinases (MMPs), leading to cartilage matrix degradation. Because it initiates an inflammatory cascade, and has been found to be increased in close proximity to inflamed or injured tissue, TNF-α inhibition is a target for pain therapy. Pro-TNF-α is expressed on the plasma membrane, then cleaved in the extracellular domain. Trimerization is required for biological activity. TNF-α acts through two receptors (TNFRs): Type I receptors (p60, p55, CD 120a) are expressed constitutively on most cell types and Type II receptors (p80, p75, CD 120b) are inducible. Popular TNF-α inhibitors act primarily to inhibit binding of TNF-α to its receptors. There are currently two major classes of TNF inhibitors: 1) monoclonal antibodies to TNF-α, which prevent binding of TNF-α to its two cell-associated signaling receptors (p55 and p75) and 2) monomeric soluble forms of p55 or p75 TNFR dimerized by linking them to an immunoglobulin (Ig) Fc fragment. These Igs bind to TNF-α with high affinity and prevent it from binding to its cell-associated receptor.
TNF inhibitors have therefore been developed for therapeutic use for orthopedic and neuromuscular disease or injury that can cause pain, such as rheumatoid arthritis. Currently therapeutic agents are delivered systemically to treat bone and cartilage related defects related to degeneration, injury, infection, malignancy or developmental malformation. TNF inhibitors currently in use are generally administered systemically via intravenous infusion and subcutaneous injection, but there are side effects of anti-TNF therapies associated with the higher doses and systemic administration that are common with these therapies. A major disadvantage of these systemic drug delivery systems is that the anti-inflammatories are delivered in buffered solutions that have short half-lives, thereby requiring repeated administration to a patient, which can result in adverse effects due to the system of delivery of relatively high doses of the drug. Unfortunately, it provides a limited quantity of agent that must move through the tissue to the target site. This method is inadequate to serve the needs of patients. Anti-TNF therapy is generally needed over an extended period of time, so repeated injections are likely to be necessary. In addition, injection site pain and reactions sometimes develop with anti-TNF agents.
Recently, there have been a number of attempts to develop an acceptable implant and methods for treating disease in a patient.
U.S. Pat. No. 6,203,813 discloses an opiate antagonist implant pellet for subcutaneous administration to a patient. According to the disclosure, the subcutaneous implant pellet releases the opiate antagonist in the patient to effectively inhibit the effects of a number of additive drugs to treat drug detoxification in a patient. The subcutaneous implant is not substantially immobilized in the tissue of a patient but is free to move about under the skin. Another drawback to this approach is that the delivery of the therapeutic agent is accomplished via the general systemic circulatory system and not it's local effect.
U.S. Pat. No. 6,735,475 discloses small implantable stimulators with at least two electrodes that are small enough to have the electrodes located adjacent to a nerve structure at least partially responsible for headache and/or facial pain. The implant works via electrical stimulation of a specified tissue and does not include a therapeutic agent component as part of the device, let alone involve delivery of a therapeutic agent to desired tissue. U.S. Pat. No. 6,735,475 describes a variety of implants, for treating headache and/or facial pain, none of which are suitable for introducing therapeutic agents to a desired tissue of a patient.
U.S. Patent Application Publication No. 20040064193 discloses an implant comprising collagen and or other bio-resorbable materials for deployment in select locations for regeneration of tissue. According to the disclosure, the implant comprises a synthetic tissue substitute material and a method and system for deploying the implant. U.S. Patent Application Publication No. 20040064193 describes a variety of implants, for regeneration of tissue, none of which are suitable for introducing therapeutic agents to a desired tissue of a patient.
U.S. Patent Application Publication No. 20050074481 discloses an implantable device comprising a polyelectrolytic complex for facilitating the healing of voids in bone, cartilage and soft tissue. According to the disclosure, the implant provides in vivo culturing of tissue cells in a diverse tissue or homogeneous lesion. U.S. Patent Application Publication No. 20050074481 describes a variety of implants, for facilitating the healing of voids in bone, cartilage and soft tissue, none of which are suitable for introducing therapeutic agents to a desired tissue of a patient.
U.S. Patent Application Publication No. 20050177118 also discloses an implantable device comprising a polyelectrolytic complex for facilitating the healing of voids in bone, cartilage and soft tissue. According to the disclosure, the implant provides in vivo culturing of tissue cells in a diverse tissue or homogeneous lesion, or for non-systemic delivery of one or more therapeutic agents to a patient. The implant provides an electrical component as part of the device and does not include a therapeutic agent component as part of the device, let alone involve delivery of a therapeutic agent to desired tissue.
U.S. Patent Application Publication No. 20050152949 discloses a method of intra-articular drug delivery comprising: selecting an attachment zone within the subchondral bone in a synovial joint, affixing a drug release device in the attachment zone, the drug release device comprising a base affixable in the attachment zone, a sustained release drug carrier and a drug, the device positioned so that the device releases the drug into the synovial fluid of the synovial joint, and so that agitation of the synovial fluid facilitates elution of the drug from the drug release device. One drawback of these implants is that they are fixedly attached to the bone itself in a synovial joint. Another drawback of these implants is that many of the intended patients already suffer from pain and inflammation, and will be subjected to more pain upon implantation of the device into the bone and possible formation of osteophytes.
Despite the advances recently made in the art, there is an immediate need for improved medical devices, methods and systems for targeted delivery of therapeutic agents, such as TNF inhibitors, for the treatment and prevention of inflammation and pain, capable of being delivered for an extended period of time at, or in close proximity to, a targeted site such as the site of trauma or inflammation.